Pharma Manufacturing

India’s top 20 pharmaceutical companies are increasing capital expenditures by 40 percent to take advantage of market opportunities to come, says a report from CRISIL, a global analytical company providing ratings, research, risk and policy advisory services. The article, which appeared on The Economic Times of India website, attributes the CapEx increase in India to the fact that the country’s “drug makers are expected to pay greater attention to regulated markets, especially the U.S. market, and to take advantage of substantial patent expiries expected in the medium term, as well as an ever-increasing demand for generics.”
There’s been no shortage of criticism of India’s pharmaceutical industry and its drug-quality lapses. A…

Vetter, well-known CMO and experienced aseptic parenteral processor, recently achieved Authorized Economic Operator Full (AEO-F) status from the European Union. Internationally accepted, AEO-F certification affirms that Vetter maintains the highest reliability, solvency and safety standards in international pharmaceutical trade. The AEO-F certificate is currently accepted by the U.S. and Japan, the EU Member States, Switzerland, Norway and China.
According to Vetter, the certification facilitates the import of drugs in third countries and confirms the quality, reliability and performance of its entire supply chain. Equipped with the AEO-F, customs procedures associated with consignments will be simplified and accelerated, “all of which…

Pharma can take inspiration from industries with mature quality systems and advanced quality capabilities

Quality has a special meaning in pharmaceuticals, where production or distribution errors can jeopardize human life. But other industries face similar challenges, and some have developed sophisticated quality systems. As pharmaceutical companies look for ways to improve their quality practices and performance, they can take ideas from these quality leaders and adapt them for pharma.
Quality can be defined in various ways, from “fitness for purpose” to “meeting customer expectations” to predictability in statistical terms. Each industry understands quality differently, and priorities depend on the specifics of products and markets. In the automotive industry, for instance, companies generally define quality as the ability to meet…

Only those pharma companies with enough courage and imagination to learn and apply lessons from other industry leaders can hope to break from the pack

Pharma managers should learn to watch their operations differently, see opportunities for improvement on their shop floor, and learn from top-performing peers and from leaders in other industries how to capture these opportunities.The pharmaceutical industry is lagging other industries in operational efficiency, as indicated by OEE ranges of 10-60 percent, up to six-month lead times, and other measures. Few pharma managers understand shop-floor operations and their potential for improvement, and few learn from their industry peers — even those whose performance is far superior. But even the best-performing pharmaceutical plant is miles away from the efficiency achieved at the average Toyota plant. Only those pharmaceutical companies and…

To combat potentially unsafe counterfeit drugs and product diversion, the FDA passed the Drug Supply Chain Security Act (DSCSA) in 2013, creating federally mandated requirements for traceability of pharmaceutical products. Fast approaching is a November 2017 DSCSA compliance deadline with additional serialization requirements. While the disruption to existing manufacturing and distribution processes will be significant, it is vital to impose supply chain visibility to prevent diversion and counterfeit products from reaching consumers.
PMMI sat down with Steve Peterson, product manager at the Peterson Group and Mario Simard, senior product line manager at Optel Vision to discuss what strategies pharmaceutical manufacturers should…

Make sure the pressure transmitters used in your CIP/SIP application are designed for that service.

In a perfect world, all the instruments used for process control would maintain their specified accuracy under any and all conditions short of damage, and maintain the same accuracy for the same process variable value regardless of what happens between measurements.
Figure 1. Repeated exposure to the high temperatures involved in CIP/SIP can cause a pressure transmitter not specifically designed for such conditions to drift out of calibration.
In the real world, instruments’ characteristics change, even if only slightly, as their operating conditions change. In sanitary processes subjected to clean-in-place (CIP) and sterilization-in-place or steam-in-place (SIP), instruments must withstand rapid changes in temperature and pressure…

The FDA has approved -- for the first time in history -- a manufacturer’s production method change from “batch” to continuous manufacturing.

Click image to enlarge
Yesterday, Lawrence Yu, FDA’s Deputy Director, wrote a blog post about a landmark event for continuous manufacturing.
The FDA has approved -- for the first time in history -- a manufacturer’s production method change from “batch” to continuous manufacturing.
This new approval is for manufacturing Janssen Products' medication for the treatment of HIV-1 infection, Prezista (darunavir), at Janssen's Gurabo, Puerto Rico, plant.
While even the FDA admits the transition from batch to continuous is "not easy," the agency is encouraged by the fact that it is seeing a growing number of manufacturers working towards building continuous manufacturing into their processes.
For Janssen, the decision to introduce CM…

The PAT (draft) Guidance was introduced in 2002, finalized in 2004, and is still largely ignored as an option by a huge number of pharma companies. Why? That is a simple question with a multi-faceted answer.
Having said that, let’s look at the money involved. PAT will cost money and time and, as the old saw goes, “time is money.” Having the money and allocating it are two different matters. While the industry still makes huge profits, it also still uses antiquated accounting and payment practices. Add to that it also considers cross-training, instrumentation/short courses and conferences as “overhead” and not necessary for this quarter’s profit.
Also, largely still in place, is the “justification” of capital spending. At…

The next decade of drug development will be based upon new and more effective means of data mining and data analytics

The pharma landscape is evolving as rapidly as the speed of technology. The industry that former FDA Commissioner Dr. McClellan admonished in 2003 with, “You need to improve!”1 has taken those words to heart to embrace innovation and technology as never before. Whether motivated by the FDA’s shift toward a scientific, data-driven definition for quality or a need to innovate to survive and be competitive in the new world marketplace, there is no doubt the push for greater understanding has resulted in a renewed emphasis on the ability to acquire, verify and leverage the power of data.
THREE DRIVERS FOR CHANGEEvery market sector needs a push sometimes to adapt and evolve. The regulated life sciences are one of the most conservative…

New xCELLigence RTCA CardioECR is the first platform for simultaneous measurement of Cardiomyocyte Contractility and Electrophysiology

Responding to the need for more predictive preclinical assays for cardiac liability, ACEA Biosciences introduced a “ground-breaking” device the company describes as “next generation.” Designated the xCELLigence RTCA CardioECR System, it is…

Are the risks of leveraging this new technology outweighing the benefits for drug makers?

Since 3D printing emerged, the technology has been used to create everything from construction materials and automobile parts to cheeseburgers and sneakers.3D printing has enormous potential across industries, and one of the most transformative applications has been in the medical field. The technology has been used to create prosthetic limbs, body tissue, dental restorations and more. In fact, as of December 2015 the FDA had cleared more than 85 3D-printed medical devices.But one of the latest medical applications – 3D printed pharmaceuticals – has called into question whether the risks of leveraging this new technology outweigh the benefits for drug makers.Manufacturing pharmaceuticals has been part of the 3D printing discussion for…

In the already diverse field of biopharmaceuticals, chemistry manufacturing and control (CMC) is about to get more complex. New formats and formulations will change CMC requirements, dictated by the need to characterize products of increased complexity and the expectation of authorities that companies will keep pace with the latest technologies so as to minimize quality risks.The potential implied changes required for an effective CMC include: more extensive information handoffs, greater cross-functional cooperation and a greater focus on relationships with regulatory agencies. These trends will demand a rethinking of the CMC setup and an appraisal of its capabilities based on a company’s product pipeline.Overarching…

In the already diverse field of biopharmaceuticals, chemistry manufacturing and control (CMC) is about to get more complex. New formats and formulations will change CMC requirements, dictated by the need to characterize products of increased complexity and the expectation of authorities that companies will keep pace with the latest technologies so as to minimize quality risks.The potential implied changes required for an effective CMC include: more extensive information handoffs, greater cross-functional cooperation and a greater focus on relationships with regulatory agencies. These trends will demand a rethinking of the CMC setup and an appraisal of its capabilities based on a company’s product pipeline.Overarching…

Converging factors are pushing drugmakers to adopt a more modern approach, and technology-enabled Product Lifecycle Management will be the key

At the product level, pharmaceutical companies are constant innovators, perpetually unveiling new and more powerful treatments for a growing range of ailments. When it comes to manufacturing, however, drugmakers are notorious for lagging other industries. (Just last year, The Wall Street Journal described pharmaceutical manufacturing processes as “dating to the days of the steam engine.”)
More specifically, pharmaceutical manufacturers have not been able to realize the benefits of Product Lifecycle Management (PLM) technology, unlike their counterparts in the discrete manufacturing world. There, PLM is a technology-enabled discipline that has connected every step in the product lifecycle, enabling radical improvements in product…

In order for biopharma companies to move quickly and adaptively enough, an outstanding project management process is critical

The global biopharmaceutical market is expected to grow at a compound annual growth rate (CAGR) of 9.4% from 2014 to 2020, reaching $278 billion in revenue by the end of this six-year period. Growth is being driven by numerous factors: such as aging populations in most of the Western world and an increased prevalence of chronic disease. However, likely the most important contributor to growth is biopharmaceutical drugs’ superior effectiveness in treating many disease states, including treating conditions for which there were previously few effective drug treatment options available.
Given the growth of the biopharmaceutical segment, and biopharmaceuticals’ ability to more precisely treat many disease states, the industry needs to…

Converging factors are pushing drugmakers to adopt a more modern approach, and technology-enabled Product Lifecycle Management will be the key

At the product level, pharmaceutical companies are constant innovators, perpetually unveiling new and more powerful treatments for a growing range of ailments. When it comes to manufacturing, however, drugmakers are notorious for lagging other industries. (Just last year, The Wall Street Journal described pharmaceutical manufacturing processes as “dating to the days of the steam engine.”)
More specifically, pharmaceutical manufacturers have not been able to realize the benefits of Product Lifecycle Management (PLM) technology, unlike their counterparts in the discrete manufacturing world. There, PLM is a technology-enabled discipline that has connected every step in the product lifecycle, enabling radical improvements in product…

Converging factors are pushing drugmakers to adopt a more modern approach, and technology-enabled Product Lifecycle Management will be the key

At the product level, pharmaceutical companies are constant innovators, perpetually unveiling new and more powerful treatments for a growing range of ailments. When it comes to manufacturing, however, drugmakers are notorious for lagging other industries. (Just last year, The Wall Street Journal described pharmaceutical manufacturing processes as “dating to the days of the steam engine.”)
More specifically, pharmaceutical manufacturers have not been able to realize the benefits of Product Lifecycle Management (PLM) technology, unlike their counterparts in the discrete manufacturing world. There, PLM is a technology-enabled discipline that has connected every step in the product lifecycle, enabling radical improvements in product…

Converging factors are pushing drugmakers to adopt a more modern approach, and technology-enabled Product Lifecycle Management will be the key

At the product level, pharmaceutical companies are constant innovators, perpetually unveiling new and more powerful treatments for a growing range of ailments. When it comes to manufacturing, however, drugmakers are notorious for lagging other industries. (Just last year, The Wall Street Journal described pharmaceutical manufacturing processes as “dating to the days of the steam engine.”)
More specifically, pharmaceutical manufacturers have not been able to realize the benefits of Product Lifecycle Management (PLM) technology, unlike their counterparts in the discrete manufacturing world. There, PLM is a technology-enabled discipline that has connected every step in the product lifecycle, enabling radical improvements in product…

Validation, calibration and qualification are extremely critical in pharmaceutical processes. Understanding them is necessary in order to meet cGMP guidelines.

Pharmaceutical facilities consist of various processes, each of which must be accurate to ensure that the end product is of high quality. While validation is concerned mainly with processes, it is referred to as a qualification when the same approach is applied to a machine or equipment instead of a process.
Why is Validation Needed?Validation is a systematic approach where it is confirmed that any process in a pharmaceutical facility will operate within the specified parameters whenever required. This is achieved by collecting and analyzing data. Validation is done to assure that the processes will produce consistent and repeatable results within the predetermined specifications.
Validation is needed as it verifies whether the quality…

Last month I walked the show floor at Pharma EXPO, executing my usual tradeshow-technology-trend spotting. It was difficult to advance more than 10 feet without hearing or reading the world “serialization.” I’m fairly certain serialization could have had its own hall at McCormick Place.
And perhaps the attention is warranted given the timing. The November 2017 DSCSA compliance deadline, after all, is a federally mandated requirement. The DSCSA will require all prescription drugs in the U.S. to have unique serial numbers to enable track and trace. This marks the first time that many pharma manufacturers and supply chain partners will have to implement serialization and manage serialized product inventory, though many are ahead of the…

The U.S. FDA, under fire for its drug approval backlog, says it has over 700 job vacanies at CDER.

The U.S. FDA, under fire for its drug approval backlog, says it has over 700 job vacanies at its Center for Drug Evaluation and Research (CDER).
At a recent industry event, Janet Woodcock said that the agency is struggling to hire and retain staff because pharmaceutical companies are offering employees much higher salaries.
CDER had 711 openings out of 5,525 positions at the end of September, said an FDA spokewoman.
Aside from salary, the speed in which the agency goes through the hiring process is a challenge. “A young person with a family can’t wait four months for us to get through some of the federal hiring process. So if they have something else that’s more . . . expedient, they will take that,” said Peter Marks,…

Validation, calibration and qualification are extremely critical in pharmaceutical processes. Understanding them is necessary in order to meet cGMP guidelines.

Pharmaceutical facilities consist of various processes, each of which must be accurate to ensure that the end product is of high quality. While validation is concerned mainly with processes, it is referred to as a qualification when the same approach is applied to a machine or equipment instead of a process.
Why is Validation Needed?Validation is a systematic approach where it is confirmed that any process in a pharmaceutical facility will operate within the specified parameters whenever required. This is achieved by collecting and analyzing data. Validation is done to assure that the processes will produce consistent and repeatable results within the predetermined specifications.
Validation is needed as it verifies whether the quality…

Converging factors are pushing drugmakers to adopt a more modern approach, and technology-enabled Product Lifecycle Management will be the key

At the product level, pharmaceutical companies are constant innovators, perpetually unveiling new and more powerful treatments for a growing range of ailments. When it comes to manufacturing, however, drugmakers are notorious for lagging other industries. (Just last year, The Wall Street Journal described pharmaceutical manufacturing processes as “dating to the days of the steam engine.”)
More specifically, pharmaceutical manufacturers have not been able to realize the benefits of Product Lifecycle Management (PLM) technology, unlike their counterparts in the discrete manufacturing world. There, PLM is a technology-enabled discipline that has connected every step in the product lifecycle, enabling radical improvements in product…

As pharma companies expand, they are looking more and more to biologics for their next potential blockbusters. However, this class of product — ranging from well-established large molecule drugs to truly novel therapies — poses major challenges because of its scientific complexity and sophisticated development requirements.Furthermore, expanding the drug pipeline isn’t the only growth strategy most companies are pursuing. They are also planning to expand geographically and expect to face various risks doing so, including unfamiliar regulatory environments, shifts in pricing and changes in customers’ ability to pay.
All this means that risk management is rising in pharma executives’ agendas. To manage risks, companies are…

New therapeutics require an error-free, integrated approach to manufacture, shipment and storage

The increasing use of CAR T-cell therapy, immunotherapy and other autologous cellular therapies necessitate an integrated approach to the manufacture, shipment and storage of these new biologic products. The need for integration is largely due to the complexity of the end-to-end process for these therapeutics, which involves obtaining cell materials from a patient, sending the materials to the manufacturing facility, and then shipping the finished product back for administration to the patient at the dispensing clinic or hospital.
The process leaves no room for error in tracking or traceability, and the materials must be shipped and stored at the prescribed temperature range, whether it is 2–8 degrees C for the inbound apheresis material…

Corrective actions are implemented to reduce future failures, but resources aren’t allocated to identify the root cause on a significant failure; This gap creates the opportunity to implement a RCFA program.

Your clean steam generator system stops and alarms. Production halts; operations quickly calls maintenance. Maintenance jumps into action and determines that the bearing seized in the feed water pump. A bearing order is expedited through procurement, maintenance efficiently makes the repair the next morning, and the production team runs tests before putting the system back into operation. Corrective actions are created to ensure that the bearing is stocked in the MRO storeroom, and to double frequency of the pump’s preventive maintenance. The senior leadership team is satisfied with the response and corrective actions, and praises the team for limiting the production delay to just 24 hours.
Does this scenario sound familiar? A critical…

Every cleanroom requires a carefully controlled environment maintained with Good Manufacturing Practices to prevent contamination

In 2012, a fungal meningitis outbreak in the United States was traced to a compounding pharmacy in the Northeast. The pharmacy distributed contaminated vials to medical facilities in 23 states. These were administered to more than 14,000 patients before anyone linked symptoms to the tainted medication.
By the time the source was isolated and the drug recalled, 48 people had died and 720 required treatment for persistent fungal infections. Investigators later discovered both procedural shortcuts and significant failures in cleaning and maintenance at the pharmacy.
This is not an isolated instance of inadequate cleanroom sanitation. The FDA maintains a well-populated list of inspections and citations conducted between 2006 and 2012 on its…

Pharma execs and facility managers are constantly exploring all possible ways to tighten their belts and bolster the company’s bottom line. A growing number are finding one path to savings runs through an often-overlooked area of their facility’s operations – its loading docks.

Pharmaceutical manufacturing is a highly competitive business, with product development, quality control, regulatory/compliance and even shareholder issues that are much more complex than in many other industries. Because of that, pharma execs and facility managers are constantly exploring all possible ways to tighten their belts and bolster the company’s bottom line. A growing number are finding one path to savings runs through an often-overlooked area of their facility’s operations – its loading docks.
When trailers are positioned at the dock being loaded or unloaded, gaps often exist between the trailer and the edges of the dock opening, through which expensive heating and cooling energy can escape, and unwanted contaminants…

Hyderabad-based API provider Neuland Labs sheds the stigma of Indian manufacturers by building stringent quality control into every process

Neuland Lab’s core business and operational expertise for more than 30 years has been the manufacturing of Active Pharmaceutical Ingredients (APIs) for the generic market as well as APIs for custom manufacturing. During that time, Neuland has become a reliable source in the pharmaceutical industry, boasting more than 400 DMFs worldwide, with 45 of those filed with the U.S. FDA.
One of the very first Indian contract manufacturers to be inspected by the U.S. FDA, back in 1997, Neuland now has two U.S. FDA- and EU GMP-compliant manufacturing facilities — one in Bonthapally and one in Pashamylaram (45,000m² and 38,000m², respectively), as well as a state-of-the-art R&D facility, with the collective ability to produce more than 75…

Sustainability lobby group Changing Markets has published a report that reveals the presence of lethal drug-resistant bacteria in water found near multiple production sites in India.

Sustainability lobby group Changing Markets has published a report that reveals the presence of lethal drug-resistant bacteria in water found near multiple production sites in India.
According to the report, analysis of water samples found high levels of drug-resistant bacteria at sites in three Indian cities: Hyderabad, New Delhi and Chennai.
Out of 34 sites tested, 16 were found to be harboring bacteria resistant to antibiotics. At four of the sites, resistance to three major classes of antibiotics was detected, including last resort antibiotics -- those used to treat infections that fail to respond to all other medicines.
The report called out Hyderabad-based Aurobindo Pharma as one of the worst offenders, saying the drugmaker is "a…

The new jobs will be in the sciences, clinical services and clinical technologies and pharmaceutical services

Ireland-based Almac Group, a CMO with U.S. headquarters in Souderton, Pennsylvania, announced it will invest $24.4 million to expand its Montgomery County, Pa., site and add 312 full-time jobs over the next three years. The company plans to expand its existing 240,000-square-foot Souderton facility and lease an additional 26,000 square feet in office space in nearby Lansdale.
The new jobs will be in the sciences, clinical services and clinical technologies and pharmaceutical services, the company said. They also plan to retain 1,110 current employees currently working there.
The Pennsylvania Department of Community and Economic Development offered funding that included a $1.56 million "first program" grant for new machine lines, computer…

There are a number of points of view and opinions on how good or necessary biosimilars actually are

As many of you know, biosimilars are, simply, proteinaceous materials, physio-chemically identical to an existing drug substance, merely generated by a differing pathway. There are a number of points of view and opinions on how good or necessary they are:
1. a. They are necessary to keep prices in check. This is always the argument for generics and has a fair amount of validity. Considering a lack of price controls in much of the United States, this is a valid point. Many newer drugs can easily reach more than $100,000 per year, per patient, so any price relief should be applauded.
So, it is claimed, it is in the interest of patients that less expensive alternative sources of a medicine be made available. Since the process of synthesis is…

Hyderabad-based API provider Neuland Labs sheds the stigma of Indian manufacturers by building stringent quality control into every process

Neuland Lab’s core business and operational expertise for more than 30 years has been the manufacturing of Active Pharmaceutical Ingredients (APIs) for the generic market as well as APIs for custom manufacturing. During that time, Neuland has become a reliable source in the pharmaceutical industry, boasting more than 400 DMFs worldwide, with 45 of those filed with the U.S. FDA.
One of the very first Indian contract manufacturers to be inspected by the U.S. FDA, back in 1997, Neuland now has two U.S. FDA- and EU GMP-compliant manufacturing facilities — one in Bonthapally and one in Pashamylaram (45,000m² and 38,000m², respectively), as well as a state-of-the-art R&D facility, with the collective ability to produce more than 75…

There are a number of points of view and opinions on how good or necessary biosimilars actually are

As many of you know, biosimilars are, simply, proteinaceous materials, physio-chemically identical to an existing drug substance, merely generated by a differing pathway. There are a number of points of view and opinions on how good or necessary they are:
1. a. They are necessary to keep prices in check. This is always the argument for generics and has a fair amount of validity. Considering a lack of price controls in much of the United States, this is a valid point. Many newer drugs can easily reach more than $100,000 per year, per patient, so any price relief should be applauded.
So, it is claimed, it is in the interest of patients that less expensive alternative sources of a medicine be made available. Since the process of synthesis is…

Just months after its $7.2B acquisition of Meda, Mylan is closing the company's U.S. headquarters in Somerset, NJ.

Just months after its $7.2B acquisition of Meda, Mylan is closing the company's U.S. headquarters in Somerset, NJ.
The closing, effective December 31 2016, will result in 94 layoffs.
Last February, Mylan agreed to buy Sweden’s Meda AB for $7.2 billion in cash and stock -- a price that represented a 92% premium -- and investors were not pleased. A large part of Mylan's attraction to the Meda deal involved acquiring Meda's European EpiPen sales, as well as its over-the-counter business. Meda turned down two previous buyout offers from Mylan in 2014. The acquisition of Meda also provides Mylan with entry into a number of new and attractive emerging markets.
Read the NJ.com release

Aseptic Blow-Fill-Seal Technology vs. Traditional Aseptic Processing

Acknowledged by the FDA as an advanced aseptic process for the packaging of sterile pharmaceutical liquids, blow-fill-seal technology is gaining increasing acceptance by providing a high assurance of product sterility, eliminating the need for human intervention, improving flexibility in container design and increasing process uptime.

Since its introduction into the North American pharmaceutical market more than 40 years ago, blow-fill-seal (BFS) aseptic processing has established itself as a highly efficient and safe system for the filling and packaging of sterile pharmaceutical liquids and other healthcare products, such as creams and ointments. BFS product usage has been widely established in the ophthalmic and respiratory therapy markets for some time, and lately BFS technology has been gaining increasing worldwide acceptance in the parenteral drug marketplace, replacing traditional glass vial processing in a growing number of applications.

BFS enables a container to be molded from plastic, aseptically filled and hermetically sealed in one continuous, integrated and automatic operation, without human manipulation. The process provides flexibility in container design and system changeovers, high volume product output, low operational costs and a high assurance of product sterility. The inherent safety of the process – packaging sterile products under aseptic conditions without human intervention – has led the FDA, and the United States Pharmacopoeia, to characterize BFS technology as an "advanced aseptic process", indicating its use as a preferred technology.

New advances in drug delivery, the desire to improve convenience in handling pharmaceutical products, growing emphasis on combination products, the increasing focus on protein-based drugs and other biologics, and tighter regulatory criteria on product safety, have focused more attention on BFS technology over traditional aseptic methods as a better solution for the sterile, aseptic processing of pharmaceutical liquids. Traditional Aseptic Processing and Sterility of Pharmaceutical Liquids

Microbial contamination is a serious issue for companies manufacturing liquid pharmaceutical formulations. Such liquids are ideal growth areas for bacteria like Salmonella, E. coli and Staphylococcus, microbes that have been found in various liquid drug products. A supposedly sterile, but contaminated product may result in deterioration of the drug and loss of potency, pyrogenic reactions after administration to a patient – particularly in parenterals, infection of the patient and colonization of microorganisms in the patient with the risk of a secondary infection. Any microorganism, pathogen or nonpathogenic, found in a supposedly sterile pharmaceutical product is dangerous.

Drug manufacturers have pursued various methods of sterilizing packaging components, product ingredients and equipment in order to achieve a sterile product in its final form. One system used is traditional processing, followed by terminal sterilization, which involves initially filling and sealing product containers within a cleanroom environment. The environment is set up to minimize the microbial content of the product while it is being manufactured. Each component of the process – the product, container and closure – have a low bioburden, but may or may not be sterile. The product, in the final container, is subjected to a “terminal” sterilization process, such as heat or radiation. The most common method uses autoclaving with saturated steam under pressure.

Traditional aseptic processing allows a final sterile drug product to be achieved by individually sterilizing the containers, material and equipment in-process, resulting in a unified sterilized product. In traditional aseptic processing, the containers are either supplied cleaned and sterilized to the filling line, or they are cleaned and sterilized within the aseptic filling line. Plastic containers are usually washed, dried, sterilized and cooled before filling. Glassware containers, which have been the dominating packaging material for terminally sterilized and traditionally sterilized pharmaceutical liquids, are usually sterilized in-line, exposed to hot air at 350 degrees C while being passed through a Class 100 tunnel. A glass container temperature of 180 to 200 degrees C is adequate for achieving sterility.

Methods of sterilization used in aseptic processing include filtering the solution by dissolving it in a solvent, such as Water For Injection (WFI), where the solution is passed through a sterilizing filter or membrane. Filter sterilization is used where the component is soluble and likely to be adversely affected by heat. A variation of this method includes subjecting the filtered solution to aseptic crystallization and precipitation (Lyophilization) of the component as a sterile powder. Dry heat sterilization is another effective method for sterilizing components that are heat stable and insoluble. Irradiation can also be used to sterilize some components.

Aseptic processing handles components, materials and equipment in such a manner that foreign microbial and endotoxin contaminents that exceed pre-determined acceptable levels, are not introduced to the product stream. To this end, it is critical that all storage, conveying, filling and container sealing stages be carefully controlled at each step of the process to maintain sterility of the product. Traditional aseptic processing, involving filling open glass bottles or vials, requires that the manufacturer maintain aseptic conditions in critical processing areas at all times. Unfortunately, the majority of liquid drug product contamination over the past several decades has come about from products produced in traditional aseptic processing facilities.

Personnel Intervention in Traditional Aseptic Critical Areas

Traditional aseptic sterilization involves handling and manipulation of the material, containers, and sterilization filling processes with human intervention, and therefore has a higher potential for contamination during processing. The FDA’s 2004 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing states that the design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel. Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures or the surrounding environment.

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